Cancer.gov | Cannabis and Cannabinoids (PDQ®)

The following was excerpted from Cancer.gov. But I must interject the OBLIVIOUS QUESTION of how come they have not updated their content with NEW research? Our Most Prestigious Universities in USA have MUCH MORE NEW RESEARCH showing Cannabinoids shrink tumors and can ultimately get rid of them, it seems not just stop there, but the hemp and medicine do wonders for many things. BUT IT IS A MAJOR CONFLICT FOR OUR CURRENT INDUSTRIES!!

Commercially available cannabinoids, such as dronabinol and nabilone, are approved for the treatment of cancer-related side effects.

Cannabinoids may have benefits in the treatment of cancer-related side effects.

Many of the medical and scientific terms used in this summary are hypertext linked (at first use in each section) to the NCI Dictionary of Cancer Terms, which is oriented toward nonexperts. When a linked term is clicked, a definition will appear in a separate window. All linked terms and their corresponding definitions will appear in a glossary in the printable version of the summary.

Reference citations in some PDQ CAM information summaries may include links to external Web sites that are operated by individuals or organizations for the purpose of marketing or advocating the use of specific treatments or products. These reference citations are included for informational purposes only. Their inclusion should not be viewed as an endorsement of the content of the Web sites, or of any treatment or product, by the PDQ Cancer CAM Editorial Board or the National Cancer Institute.

General Information

Cannabis, also known as marijuana, originated in Central Asia but is grown worldwide today. In the United States, it is a controlled substance and is classified as a Schedule I agent (a drug with increased potential for abuse and no known medical use). The Cannabis plant produces a resincontaining psychoactive compounds called cannabinoids. The highest concentration of cannabinoids is found in the female flowers of the plant.[1] Clinical trials conducted on medicinal Cannabis are limited. The U.S. Food and Drug Administration (FDA) has not approved the use of Cannabis as a treatment for any medical condition. To conduct clinical drug research in the United States, researchers must file an Investigational New Drug (IND) application with the FDA.

The potential benefits of medicinal Cannabis for people living with cancer include antiemetic effects,appetite stimulation, pain relief, and improved sleep. Although few relevant surveys of practice patterns exist, it appears that physicians caring for cancer patients in the United States who recommend medicinal Cannabis predominantly do so for symptom management.[2]

Cannabinoids are a group of terpenophenolic compounds found in Cannabis species (Cannabis sativa L. and Cannabis indica Lam.). This summary will review the role of Cannabis and the cannabinoids in the treatment of people with cancer and disease-related or treatment-related side effects.

HistoryCannabis use for medicinal purposes dates back at least 3,000 years.[1–5] It was introduced intoWestern medicine in the 1840s by W.B. O’Shaughnessy, a surgeon who learned of its medicinal properties while working in India for the British East Indies Company. Its use was promoted for reported analgesic, sedative, anti-inflammatory, antispasmodic, and anticonvulsant effects.

In 1937, the U.S. Treasury Department introduced the Marihuana Tax Act. This Act imposed a levy of one dollar an ounce for medicinal use of Cannabis and one hundred dollars an ounce for recreational use. Physicians in the United States were the principal opponents of the Act. The American Medical Association (AMA) opposed the Act because physicians were required to pay a special tax forprescribing Cannabis, use special order forms to procure it, and keep special records concerning its professional use. In addition, the AMA believed that objective evidence that Cannabis was harmful was lacking and that passage of the Act would impede further research into its medicinal worth.[6] In 1942, Cannabis was removed from the U.S. Pharmacopoeia because of persistent concerns about its potential to cause harm.[2,3]

In 1951, Congress passed the Boggs Act, which for the first time, included Cannabis with narcoticdrugs. In 1970, with the passage of the Controlled Substances Act, marijuana was classified as a Schedule I drug. Drugs in this category are distinguished as having no accepted medicinal use. Other Schedule I substances include heroin, LSD, mescaline, methaqualone, and gamma-hydroxybutyrate.

Despite its designation as having no medicinal use, Cannabis was distributed to patients by the U.S. government on a case-by-case basis under the Compassionate UseInvestigational New Drug program established in 1978. Distribution of Cannabis through this program was discontinued in 1992.[1–4] To date, medical Cannabis use is regulated by law in 16 states and the District of Columbia.

The main psychoactive constituent of Cannabis was identified as delta-9-tetrahydrocannabinol (THC). In 1986, synthetic delta-9-THC in sesame oil was licensed and approved for the treatment ofchemotherapy -associated nausea and vomiting under the generic name dronabinol. Clinical trialsdetermined that dronabinol was as effective as or better than other antiemetic agents available at the time.[7] Dronabinol was also studied for its ability to stimulate weight gain in patients with AIDS in the late 1980s. Thus, the indications were expanded to include treatment of anorexia associated with human immunodeficiency virus infection in 1992. Clinical trial results showed no statisticallysignificant weight gain, although patients reported an improvement in appetite.[8,9]

Within the past 20 years, the neurobiology of cannabinoids has been analyzed.[10–13] The first cannabinoid receptor, CB1, was pharmacologically identified in the brain in 1988. A second cannabinoid receptor, CB2, was identified in 1993. The highest concentration of CB2 receptors is located on B lymphocytes and natural killer cells, suggesting a possible role in immunity.Endogenous cannabinoids (endocannabinoids) have been identified and appear to have a role in pain modulation, control of movement, feeding behavior, and memory.[11]

References

Abel EL: Marihuana, The First Twelve Thousand Years. New York: Plenum Press, 1980. Also available online. Last accessed July 7, 2011.

Schaffer Library of Drug Policy.: The Marihuana Tax Act of 1937: Taxation of Marihuana. Washington, DC: House of Representatives, Committee on Ways and Means, 1937. Available online. Last accessed July 7, 2011.

Cannabinoids are a group of 21-carbon–containing terpenophenolic compounds produced uniquely by Cannabis sativa and Cannabis indica species.[1,2] These plant-derived compounds may be referred to as phytocannabinoids. Although delta-9-tetrahydrocannabinol (THC) is the primary psychoactive ingredient, other known compounds with biologic activity are cannabinol, cannabidiol (CBD), cannabichromene, cannabigerol, tetrahydrocannabivarin, and delta-8-THC. CBD, in particular, is thought to have significantanalgesic and anti-inflammatory activity without the psychoactive effect (high) of delta-9-THC.

Cannabinoids may cause antitumor effects by various mechanisms, including induction of celldeath, inhibition of cell growth, and inhibition of tumorangiogenesis and metastasis.[9–11] Cannabinoids appear to kill tumor cells but do not affect their nontransformed counterparts and may even protect them from cell death. These compounds have been shown to induce apoptosis inglioma cells in culture and induce regression of glioma tumors in mice and rats. Cannabinoids protect normal glial cells of astroglial and oligodendroglial lineages from apoptosis mediated by the CB1 receptor.[12]

In an in vivo model using severe combined immunodeficient mice, subcutaneous tumors were generated by inoculating the animals with cells from human non-small cell lungcarcinomacell lines.[13] Tumor growth was inhibited by 60% in THC-treated mice compared with vehicle-treated control mice. Tumor specimens revealed that THC had antiangiogenic and antiproliferative effects. However, research with immunocompetent murine tumor models has demonstrated immunosuppression and enhanced tumor growth in mice treated with THC.[14,15]

In addition, both plant-derived and endogenous cannabinoids have been studied for anti-inflammatory effects. A mouse study demonstrated that endogenous cannabinoid system signaling is likely to provide intrinsic protection against colonic inflammation.[16] As a result, a hypothesis that phytocannabinoids and endocannabinoids may be useful in the prevention and treatment ofcolorectal cancer has been developed.[17–20]

Appetite StimulationMany animal studies have previously demonstrated that delta-9-THC and other cannabinoids have a stimulatory effect on appetite and increase food intake. It is believed that the endogenous cannabinoid system may serve as a regulator of feeding behavior. The endogenous cannabinoid anandamide potently enhances appetite in mice.[21] Moreover, CB1 receptors in the hypothalamusmay be involved in the motivational or reward aspects of eating.[22]

AnalgesiaUnderstanding the mechanism of cannabinoid-induced analgesia has been increased through the study of cannabinoid receptors, endocannabinoids, and synthetic agonists and antagonists. The CB1 receptor is found in both the central nervous system (CNS) and in peripheral nerve terminals. Similar to opioid receptors, increased levels of the CB1 receptor are found in regions of the brain that regulate nociceptive processing.[23] CB2 receptors, located predominantly in peripheral tissue, exist at very low levels in the CNS. With the development of receptor-specific antagonists, additional information about the roles of the receptors and endogenous cannabinoids in the modulation of pain has been obtained.[24,25]

Cannabinoids may also contribute to pain modulation through an anti-inflammatory mechanism; a CB2 effect with cannabinoids acting on mast cell receptors to attenuate the release of inflammatory agents, such as histamine and serotonin, and on keratinocytes to enhance the release of analgesicopioids has been described.[26–28]

When Cannabis is ingested by mouth, there is a low (6%–20%) and variable oralbioavailability.[1,2] Peak plasma concentrations of delta-9-tetrahydrocannabinol (THC) occur after 1 to 6 hours and remain elevated with a terminal half-life of 20 to 30 hours. Taken by mouth, delta-9-THC is initially metabolized in the liver to 11-OH-THC, a potent psychoactive metabolite. When inhaled, cannabinoids are rapidly absorbed into the bloodstream with a peak concentration in 2 to 10 minutes, declining rapidly for a period of 30 minutes and with less generation of the psychoactive 11-OH metabolite.

A number of studies have yielded conflicting evidence regarding the risks of various cancers associated with Cannabis use.

A pooled analysis of three case-cohort studies of men in northwestern Africa (430 cases and 778 controls) showed a significantly increased risk of lung cancer among tobacco smokers who also inhaled Cannabis.[5]

A large retrospective cohort study of 64,855 men aged 15 to 49 years from the United States found that Cannabis use was not associated with tobacco-related cancers and a number of other common malignancies. However, the study did find that, among nonsmokers of tobacco, ever having usedCannabis was associated with an increased risk of prostate cancer.[6]

A population-based case-control study of 611 lung cancer patients revealed that chronic lowCannabis exposure was not associated with an increased risk of lung cancer or other upperaerodigestive tract cancers and found no positive associations with any cancer type (oral, pharyngeal,laryngeal, lung, or esophagus) when adjusting for several confounders, including cigarette smoking.[7]

A comprehensive Health Canada monograph on marijuana concluded that while there are many cellular and molecular studies that provide strong evidence that inhaled marijuana is carcinogenic, the epidemiologic evidence of a link between marijuana use and cancer is still inconclusive.[9]

Cancer Treatment

No clinical trials of Cannabis as a treatment for cancer in humans were identified in a PubMed search; however, a single small study of intratumoral injection of delta-9-THC in patients with recurrent glioblastoma multiforme reported potential antitumoral activity.[10]

Antiemetic Effect

Cannabinoids

Despite advances in pharmacologic and nonpharmacologic management, nausea and vomiting (N/V) remain distressing side effects for cancer patients and their families. Dronabinol was approved in the United States in 1986 as an antiemetic to be used in cancer chemotherapy. Nabilone, anothersynthetic derivative of delta-9-THC, was first approved in Canada in 1982 and is now also available in the United States.[11] Both dronabinol and nabilone have been approved by the U.S. Food and Drug Administration for the treatment of N/V associated with cancer chemotherapy in patients who have failed to respond to conventional antiemetic therapy. Numerous clinical trials and meta-analyses have shown that dronabinol and nabilone are effective in the treatment of N/V induced by chemotherapy.[12–15] The National Comprehensive Cancer Network Guidelines recommend cannabinoids as breakthrough treatment for chemotherapy-related N/V.

One systematic review studied 30 randomized comparisons of delta-9-THC preparations with placeboor other antiemetics from which data on efficacy and harm were available.[16] Oral nabilone, oral dronabinol, and intramuscular levonantradol (a synthetic analog of dronabinol) were tested. InhaledCannabis trials were not included. Among all 1,366 patients included in the review, cannabinoids were found to be more effective than the conventional antiemetics prochlorperazine, metoclopramide, chlorpromazine, thiethylperazine, haloperidol, domperidone, and alizapride. Cannabinoids, however, were not more effective for patients receiving very low or very high emetogenic chemotherapy. Side effects included a feeling of being high, euphoria, sedation or drowsiness, dizziness, dysphoria ordepression, hallucinations, paranoia, and hypotension.[16] Newer antiemetics (e.g., 5-HT3 receptor antagonists) have not been directly compared with Cannabis or cannabinoids in cancer patients.

Another analysis of 15 controlled studies compared nabilone with placebo or available antiemetic drugs.[17] Among 600 cancer patients, nabilone was found to be superior to prochlorperazine, domperidone, and alizapride, with nabilone favored for continuous use.

Three trials have evaluated the efficacy of inhaled marijuana in chemotherapy-induced N/V.[18–20] In two of the studies, inhaled Cannabis was made available only after dronabinol failure. In the first trial, no antiemetic effect was achieved with marijuana in patients receiving cyclophosphamide ordoxorubicin,[18] but in the second trial, a statistically significant superior antiemetic effect of inhaledCannabis was found among patients receiving high- dosemethotrexate compared with those receiving placebo.[19] The third trial was a randomized, double-blind, placebo-controlled cross-over trial involving 20 adults in which both inhaled marijuana and oral THC were evaluated. One-quarter of the patients reported a favorable antiemetic response to the cannabinoid therapies. This latter study was reported in abstract form in 1984. A full report, detailing the methods and outcomes apparently has not been published, which limits a thorough interpretation of the significance of these findings.[20]

Appetite Stimulation

Anorexia, early satiety, weight loss, and cachexia are problems experienced by cancer patients. Such patients are faced not only with the disfigurement associated with wasting but also with an inability to engage in the social interaction of meals.

Cannabinoids

Two controlled trials demonstrated that oral THC has variable effects on appetite stimulation and weight loss in patients with advanced malignancies and human immunodeficiency virus (HIV)infection.[17] One study evaluated whether dronabinol alone or with megestrolacetate was greater, less, or equal in efficacy to megestrol acetate alone for managing cancer-associated anorexia.[21] In this randomized double-blind study of 469 adults with advanced cancer and weight loss, patients received 2.5 mg of oral THC twice daily, 800 mg of oral megestrol daily, or both. Appetite increased by 75% in the megestrol group and weight increased by 11%, compared with a 49% increase in appetite and a 3% increase in weight in the oral THC group after 8 to 11 weeks of treatment. These two differences were statistically significant. Furthermore, the combined therapy did not offer additional benefits beyond those provided by megestrol acetate alone. The authors concluded that dronabinol did little to promote appetite or weight gain in advanced cancer patients compared with megestrol acetate. However, a smaller placebo-controlled trial of dronabinol in cancer patients demonstrated improved and enhanced chemosensory perception in the cannabinoid group—food tasted better, appetite increased, and the proportion of calories consumed as protein was greater than in the placebo recipients.[22]

Another clinical trial that involved 139 patients with HIV or AIDS and weight loss found that, compared with placebo, oral dronabinol was associated with a statistically significant increase in appetite after 4 to 6 weeks of treatment. Patients receiving dronabinol tended to have weight stabilization, whereas patients receiving placebo continued to lose weight.[23]

Cannabis

In trials conducted in the 1980s that involved healthy control subjects, inhaling Cannabis led to an increase in caloric intake, mainly in the form of between-meal snacks, with increased intakes of fatty and sweet foods.[24,25] No published studies have explored the effect of inhaled Cannabis on appetite in cancer patients.

Analgesia

Cannabinoids

Pain management improves a patient’s quality of life throughout all stages of cancer. Through the study of cannabinoid receptors, endocannabinoids, and synthetic agonists and antagonists, the mechanisms of cannabinoid-induced analgesia have been analyzed. The CB1 receptor is found in the central nervous system (CNS) and in peripheral nerve terminals.[26] CB2 receptors are located mainly in peripheral tissue and are expressed in only low amounts in the CNS. Whereas only CB1 agonists exert analgesic activity in the CNS, both CB1 and CB2 agonists have analgesic activity in peripheral tissue.[27,28]

Cancer pain results from inflammation, invasion of bone or other pain-sensitive structures, or nerve injury. When cancer pain is severe and persistent, it is often resistant to treatment with opioids.

Two studies examined the effects of oral delta-9-THC on cancer pain. The first, a double-blind placebo- controlled study involving ten patients, measured both pain intensity and pain relief.[29] It was reported that 15 mg and 20 mg doses of the cannabinoid delta-9-THC were associated with substantial analgesic effects, with antiemetic effects and appetite stimulation.

In a follow-up single-dose study involving 36 patients, it was reported that 10 mg doses of delta-9-THC produced analgesic effects during a 7-hour observation period that were comparable to 60 mg doses of codeine, and 20 mg doses of delta-9-THC induced effects equivalent to 120 mg doses of codeine.[30] Higher doses of THC were found to be more sedative than codeine.

Another study examined the effects of a whole-plant extract with controlled cannabinoid content in an oromucosal spray. In a multicenter, double-blind, placebo-controlled study, the THC:cannabidiol (THC:CBD) extract and THC extract alone were compared in the analgesic management of patients with advanced cancer and with moderate-to-severe cancer-related pain. Patients were assigned to one of three treatment groups: THC:CBD extract, THC extract, or placebo. The researchers concluded that the THC:CBD extract was efficacious for pain relief in advanced cancer patients whose pain was not fully relieved by strong opioids.[31]

Neuropathic pain is a symptom cancer patients may experience, especially if treated with platinum-based chemotherapy or taxanes. A randomized controlled trial of inhaled Cannabis compared with placebo in 50 patients with HIV-related peripheral neuropathy found that pain was reduced by more than 30% in 52% of patients in the Cannabis group and in 24% of patients in the placebo group. This difference was statistically significant.[33] To date, no clinical trial has examined the effectiveness of cannabinoid preparations in the treatment of chemotherapy-induced neuropathic pain.

Anxiety and Sleep

Cannabis

Patients often experience mood elevation after exposure to Cannabis, depending on their prior experience. In a five-patient case series of inhaled marijuana that examined the analgesic effects of THC, it was reported that patients administered THC had improved mood, improved sense of well-being, and less anxiety.[34]

Another common effect of Cannabis is sleepiness. In a trial of a sublingual spray, a Cannabis-based mixture was able to improve sleep quality.[35] A small placebo-controlled study of dronabinol in cancer patients with altered chemosensory perception also noted increased quality of sleep and relaxation in THC-treated patients.[22]

Although cannabinoids are considered by some to be addictive drugs, their addictive potential is considerably lower than that of other prescribed agents or substances of abuse.[4] The brain develops a tolerance to cannabinoids.

Withdrawal symptoms such as irritability, insomnia with sleep electroencephalogram disturbance, restlessness, hot flashes, and, rarely, nausea and cramping have been observed. However, these symptoms appear to be mild compared with withdrawal symptoms associated with opiates or benzodiazepines, and the symptoms usually dissipate after a few days.

Unlike other commonly used drugs, cannabinoids are stored in adipose tissue and excreted at a low rate (half-life 1–3 days), so even abrupt cessation of cannabinoid intake is not associated with rapid declines in plasma concentrations that would precipitate severe or abrupt withdrawal symptoms or drug cravings.

Describe clinical findings in sufficient detail for a meaningful evaluation to be made.

Separate levels of evidence scores are assigned to qualifying human studies on the basis of statistical strength of the study design and scientific strength of the treatment outcomes (i.e.,endpoints) measured. The resulting two scores are then combined to produce an overall score. An overall level of evidence score cannot be assigned to cannabinoids because there has been insufficient clinical research to date. For an explanation of possible scores and additional information about levels of evidence analysis of CAM treatments for people with cancer, refer to Levels of Evidence for Human Studies of Cancer Complementary and Alternative Medicine.

There have been only three small clinical trials on the use of Cannabis in cancer patients. All three studies assessed antiemetic activity but each explored a different patient population and chemotherapy regimen. One study demonstrated no effect, the second study showed a positive effect versus placebo, and the report of the third study did not provide enough information to characterize the overall outcome as positive or neutral. Consequently, there are insufficient data to provide an overall level of evidence assessment for the use of Cannabis for chemotherapy-induced N/V. Apparently, there are no published data on the use of Cannabis for other cancer-related or cancer treatment–related symptoms.

An increasing number of trials are evaluating the sublingual administration of whole Cannabisplant extract with fixed concentrations of cannabinoid components.

At present, there is insufficient evidence to recommend inhaling Cannabis as a treatment for cancer-related symptoms or cancer treatment–related side effects outside the context of well-designed clinical trials.

The PDQcancer information summaries are reviewed regularly and updated as new information becomes available. This section describes the latest changes made to this summary as of the date above.

In writing Cancer Information Summaries, PDQ Editorial Boards review current evidence. They do not make recommendations. Their work is editorially independent of the National Cancer Institute (NCI). The summary on Cannabis and cannabinoids does not represent a policy statement of NCI or NIH. The summary statement represents an independent review of the literature; that review is not influenced by NCI or any other federal agency.

Added text to state that, by federal law, the possession of Cannabis, also known as marijuana, is illegal in the United States. Added text to state that the U.S. Food and Drug Administration has not approved Cannabis as a treatment for cancer or any other medical condition. Also added text to state that commercially available cannabinoids, such as dronabinol and nabilone, are approved for the treatment of cancer-related side effects.

Revised text to clarify that, although few relevant surveys of practice patterns exist, it appears that physicians caring for cancer patients in the United States who recommend medicinal Cannabispredominantly do so for symptom management (cited Doblin et al. as reference 2).

Added text to state that to date, medical Cannabis use is regulated by law in 16 states and the District of Columbia.

Revised text to clarify that clinical trials determined that dronabinol was as effective as or better than other antiemetic agents available at the time. Also added text to state that the indications were expanded to include treatment of anorexia associated with human immunodeficiency virus infection in 1992.

Added text to state that a single small study of intratumoral injection of delta-9-THC in patients with recurrent glioblastoma multiforme reported potential antitumoral activity (cited Guzmán et al. as reference 10).

Added text to state that the National Comprehensive Cancer Network Guidelines recommend cannabinoids as breakthrough treatment for chemotherapy-related nausea and vomiting (N/V).

Added text to state that newer antiemetics have not been directly compared with Cannabis or cannabinoids in cancer patients.

Revised text to clarify that in a second trial, a statistically significant superior antiemetic effect of inhaled Cannabis was found among patients receiving high-dose methotrexate compared with those receiving placebo.

Revised text to clarify that appetite increased by 75% in the megestrol group and weight increased by 11%, compared with a 49% increase in appetite and a 3% increase in weight in the oral THC group after 8 to 11 weeks of treatment.

Revised text to clarify that, in trials conducted in the 1980s that involved healthy control subjects, inhaling Cannabis led to an increase in caloric intake, mainly in the form of between-meal snacks, with increased intakes of fatty and sweet foods (cited 1986 Foltin et al. as reference 24 and 1988 Foltin et al. as reference 25).

Revised text to clarify that both dronabinol and nabilone are approved by the U.S. Food and Drug Administration for the prevention or treatment of chemotherapy-induced N/V in cancer patients but not for other symptom management or off-label use.

Information about complementary and alternative forms of treatment for patients with cancer.

Important:

This information is intended mainly for use by doctors and other health care professionals. If you have questions about this topic, you can ask your doctor, or call the Cancer Information Service at 1-800-4-CANCER (1-800-422-6237).

About This PDQ Summary

Purpose of This Summary

This PDQ cancer information summary for health professionals provides comprehensive, peer-reviewed, evidence-based information about the use of Cannabis and cannabinoids in the treatment of people with cancer. It is intended as a resource to inform and assist clinicians who care for cancer patients. It does not provide formal guidelines or recommendations for making health care decisions.

Changes to the summaries are made through a consensus process in which Board members evaluate the strength of the evidence in the published articles and determine how the article should be included in the summary.

The lead reviewer for Cannabis and Cannabinoids is:

Donald I. Abrams, MD (UCSF Osher Center for Integrative Medicine)

Any comments or questions about the summary content should be submitted to Cancer.gov through the Web site’s Contact Form. Do not contact the individual Board Members with questions or comments about the summaries. Board members will not respond to individual inquiries.

Levels of Evidence

Some of the reference citations in this summary are accompanied by a level-of-evidence designation. These designations are intended to help readers assess the strength of the evidence supporting the use of specific interventions or approaches. The PDQ Cancer Complementary and Alternative Medicine Editorial Board uses a formal evidence ranking system in developing its level-of-evidence designations.

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